DESCRIPTION: Age-related nuclear (ARM) cataract is a major cause of world blindness. There has been a revolution in our understanding of ARN cataract in the past few years. Up until that time, essentially all that was known was that ARN cataract was associated with profound oxidation, insolubilization, coloration and cross-linking of lens proteins. It was unclear why such oxidative changes occurred in the nuclei of these lenses. Recent advances suggest that ARN cataract develops as a direct result of changes in the lens that occur with age. (These include the discovery of a reason for lens coloration and also the biochemical/physical basis that allows oxidation in the centre of the lens to proceed; resulting ultimately in cataract.) Briefly, a barrier to the movement of the antioxidant, glutathione from its site of synthesis or reduction in the cortex, into the lens nucleus, forms in older individuals. Thus the nucleus of the older normal human lens becomes susceptible to oxidative stress. These findings suggest that most, if not all, of the features of ARN cataract may be explained on the basis of the onset of the lens barrier in middle age and the subsequent oxidation and reaction of the nuclear proteins with reactive molecules, such as UV filters. We propose to investigate the reason for the onset of the barrier at middle age. In December 2004 we showed that the nucleus of normal lenses undergoes a massive increase in hardness with age. Could this be the reason for the development of the barrier? It is the aim of this grant application to investigate this proposal. If confirmed, this would have major implications for future cataract treatment, since it offers hope that drug intervention may be possible to prevent, or delay, ARN cataract. Since the lens nucleus must undergo a major change in shape on accommodation, understanding the molecular basis of this enormous hardening may also impact on our understanding of presbyopia. [unreadable] [unreadable] [unreadable] [unreadable]